Mantle Cell Lymphoma - European Society for Medical Oncology

MANTLE CELL LYMPHOMA

Dr Tobias Weiglein, MD, MHBA & Prof Dr Martin Dreyling, MD

Ludwigs-Maximilians University Munich, Medical Department for

Hemathology and Oncology,

Campus Groβhadern, Munich, Germany

1. To understand the biology of MCL

2. To understand the diagnostic and prognostic factors in MCL

3. To choose the most appropriate first line treatment for different subsets of patients

4. To know about molecular targeted substances and therapy concepts at relapse

and refractory disease

LEARNING OBJECTIVES

Accounts for approximately 6% of all NHL cases

Median age 60-70 years

Male predominance (men > women 3:1)

Very frequent extranodal disease manifestation

Since its worldwide recognition in 1994, it has been known to have a dismal

prognosis (“the worst lymphoma to have”), with a median overall survival (OS) rate

of 3 years only


Epidemiology and characteristics

PROGNOSIS OF MANTLE CELL LYMPHOMA

PROGNOSIS OF MCL

Overall survival of MCL compared to other B-NHL entities

Survival of B-cell lymphoma subtypes in the series of the Oncology Institute of Southern Switzerland,1980-2006.

Republished with permission of American Society of Hematology, from Blood, Ghielmini M, et al., Blood, 114, 8, 2009, permission conveyed through Copyright

Clearance Center, Inc.


HISTOLOGY

A classical; B small cell; C pleomorphic; D: blastoid; E: classical & pleomorphic; F: classical/pleomorphic

Tiemann M, et al., Br J Haematol 2005;131(1):29–38. Histopathology, cell proliferation indices and clinical outcome in 304 patients with mantle cell lymphoma

(MCL): a clinicopathological study from the European MCL Network. © 2005 Blackwell Publishing Ltd.

MANTLE CELL LYMPHOMA BIOLOGY

RB signal pathway in MCL I

G1

S

G2

MRB

RB P

cdk4/

cyclin D1

MANTLE CELL LYMPHOMA:

A SPECTRUM OF DISEASE

“Indolent” MCL (15%) “Classical” MCL (80%) “Transformed” (5%)

Dreyling M, ASCO Educational 2014. Courtesy of Prof Martin Dreyling

MANTLE CELL LYMPHOMA:

TWO KINDS OF DISEASE?

Dreyling M, ESMO CR 2017. Courtesy of Prof Martin Dreyling

PROGNOSIS OF MCL

In 1980 -1990s overall median survival (OS) was

dismal with 2-4 years at time of diagnosis

Prognosis depending on clinical variables

Age

Stage

Performance Score

LDH

And biological features

Proliferation Index (Ki67)

growth pattern (blastoid vs. classical)

Tiemann M, et al., Br J Haematol 2005;131(1):29–38. Histopathology, cell proliferation indices and clinical outcome in 304 patients with mantle cell lymphoma

(MCL): a clinicopathological study from the European MCL Network. © 2005 Blackwell Publishing Ltd.

PROGNOSIS OF MCL

Risk factor proliferation: MCL 35

Scott DW, J Clin Oncol, 35(15) 2017: 1668–77. Reprinted with permission. © 2017 American Society of Clinical Oncology. All rights reserved.

MIPI:

Age

ECOG Performance status

LDH level

WBC count

MIPI-c:

MIPI + Ki-67 index

The more refined combined MIPI (MIPI-c) classifies MCL patients into four prognostic groups

dependent on MIPI group and Ki-67 index

According to MIPI-c, patients are assigned to the low, low-intermediate, high-intermediate, or

high risk group

PROGNOSIS OF MCL

MIPI and MIPI-c

Dreyling M, et al., Haematologica 2016;101(2):104–114. Obtained from the Haematologica Journal website http://www.haematologica.org;

Hoster, J Clin Oncol 2016;34(12):1386-94.

MIPI

high

MIPI

low

MIPI

intermediate

MIPI-c

high

MIPI-c

high-intermediate

MIPI-c

low-intermediate

MIPI-c

low

Ki67

<30%

Ki67

≥30%

Ki67

<30%

Ki67

≥30%

Ki67

<30%

Ki67

≥30%

PROGNOSIS OF MCL

Combined MIPI (MIPI-c)

Patients >65 years Patients <65 years

Hoster E, J Clin Oncol, 34(12), 2016:1386-94. Reprinted with permission. © 2016 American Society of Clinical Oncology. All rights reserved.

MANTLE CELL LYMPHOMA TREATMENT


TREATMENT

Optimal treatment for MCL?

=> MRD elimination=> lymphoma remission

Immuno-chemotherapy !

Maintenance

+/-

SCT

Induction Consolidation


TREATMENT

Young, fit patients

Young Fit Patient (<65)Organ Function

Comorbidity

Performance Status

Old Fit Patient (>65)Organ Function

Comorbidity

Performance Status

Old Unfit Patient (>65)Organ Function

Comorbidity

Performance Status

First Line Therapy*

Mild Therapy

e.g. R-Chlorambucil

B-R

R-CVP

Best Supportive Care?

Conventional

Immunochemotherapy

e.g. R-CHOP, B-R

VR -CAP

+ Rituximab Maintenance

Dose-intensified

Immunochemotherapy

R-CHOP / R- DHAP followed by

Autologous SCT

+ R- Maintenance

Intensive Therapy:

Long Term Survival

Less Intensive Therapy:

Remission and Better Survival

Mild Supportive Therapy:

Symptom Control , Survival

*Watch and Wait Strategy in Indolent, Low Tumour Burden Patients Possible


TREATMENT

Role of anti-CD-20 antibody rituximab

Adding rituximab to CHOP clearly

improves PFS an ORR, (ORR 94%

vs. 75%, CR 34% vs. 7%)

Improvement of ORR and PFS with

addition of rituximab to

polychemotherapy have been

confirmed in successive trials

R-Chemo standard of care in first

and successive treatment lines

1. Hoster E, et al., Blood 2008;112(11):3049. Presented at ASH Annual Meeting 2008. Courtesy of Prof Martin Dreyling;

2. Buske C, et al., 2009 Leukemia 2009;23:153–161.


TREATMENT

Why CHOP?

From N Engl J Med, Kluin-Nelemans HC, et al. Treatment of older patients with mantle-cell lymphoma, 367,520–31. Copyright © 2012 Massachusetts Medical

Society. Reprinted with permission from Massachusetts Medical Society.

MANTLE CELL LYMPHOMA TREATMENT

Autologous SCT and IFN survival rates

Treat-

ment

Hazard

Ratio 95% CI p

R 0.70 0.44 1.12 0.14

ASCT 0.63 0.41 0.97 0.0379

Treat-

ment

Hazard

Ratio 95% CI p

R 0.60 0.42 0.86 0.0056

ASCT 0.50 0.35 0.70 0.0001

Remission duration Overall survival

Dreyling M, et al., Blood 2005;105:2677–2684; Hoster E, et al. Blood 2009;114(22):880.

Presented at ASH Annual Meeting 2008 Courtesy of Prof Martin Dreyling.


TREATMENT

Young fit patients <65 years

PR, CR!3 x R-CHOP

DexaBEAM(stem cell mobilisation)

Cyclo 120 mg/kg

+ TBI 12 Gy

PBSCT

3 x R-CHOP

PR, CR!

3 x R-CHOP

3 x R-DHAP

alternating

(stem cell mobilisation

after course 4)

PBSCT

TBI 10 Gy

Ara-C 4 x 1.5 g/m2

Melphalan 140 mg/m2

Hermine O, et al., Lancet 2016;388(10044):565–75.


TREATMENT

Time to treatment failure in “MCL younger” trial

From The Lancet, 388(10044), Hermine O, et al. ( Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients

aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network,

388:565–75. Copyright © 2016 with permission from Elsevier.


TREATMENT

MRD at end of induction: Effect of ASCT

R-CHOP R-DHAP

PB BM PB BM0

25

50

75

100

% M

RD

neg

ativ

e

58%

70%

p = 0.08 p = 0.007

37%

60%

83% 79% 70%

85%

ns

**

* *

* p = 0.03

Hermine O, et al., Lancet. 2016;388(10044):565–75.


TREATMENT

Post ASCT rituximab maintenance: “LyMa” trial

R-BEAM

Rituximab maintenance

every 2 months during 3 years

Observation

R-DHAP R-DHAPR-DHAP R-DHAP

If < VGPR

W1 W4 W7 W10

R-DHAP: Rituximab 375 mg/m2; aracytine 2 g/m2 x2 IV 3 hours injection 12 hours interval; dexamethasone 40 mg d1-

4; Cisplatin 100 mg/m2 d1 (or oxaliplatin or carboplatin)

R-BEAM: Rituximab 500 mg/m2 d-8; BCNU 300 mg/m2 d-7; Etoposide 400 mg/m2/d d-6 to -3; aracytine 400 mg/m2/d d-6

to d-3; melphalan 140 mg/m2 d-2

If > VGPR

R-CHOP

Le Gouill S, et al. N Engl J Med. 2017;377(13):1250-1260


TREATMENT

Post ASCT rituximab maintenance: “LyMa” trial

From N Engl J Med, Le Gouill S, et al. Rituximab after Autologous Stem-Cell Transplantation in Mantle-Cell Lymphoma, 377, 1250–60. Copyright © 2017

Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.


TREATMENT

First line treatment young patients: Conclusion

Watch and wait strategy in indolent, low tumour burden patients possible

Rituximab – chemo is standard of care in any induction therapy

Induction-regimes containing high-dose cytarabin seem to further improve PFS, OS and MRD

negativity. ORR is 80-90% with 40-50% CR

High-dose chemotherapy, followed by autologous stem cell transplantation prolongs PFS and

OS and is the current standard of care for younger patients, generally providing high responses

and long survival rates, but is hampered by acute and long-term toxicity

R-hyper-CVAD or R-HD-MTX-Ara-C regimen, followed by a consolidation with BEAM and ASCT

is an alternative dose intensified (and toxic) approach and are debated, especially between

European and American clinical groups

Rituximab maintenance every 2 months for 3 years after ASTC improves OS


TREATMENT

Older patients / Unfit patients


Comorbidity

Performance Status


Comorbidity

Performance Status


Comorbidity

Performance Status

First Line Therapy*

Mild Therapy

e.g. R-Chlorambucil

B-R

R-CVP

Best Supportive Care?

Conventional

Immunochemotherapy

e.g. R-CHOP, B-R

VR -CAP

+ Rituximab Maintenance

Dose-intensified

Immunochemotherapy

R-CHOP / R- DHAP followed by

Autologous SCT

+ R- Maintenance

Intensive Therapy:

Long Term Survival

Less Intensive Therapy:

Remission and Better Survival

Mild Supportive Therapy:

Symptom Control , Survival

*Watch and Wait Strategy in Indolent, Low Tumour Burden Patients Possible

IMMUNO-CHEMOTHERAPY IN

ELDERLY >65 YEARS

Progression-free survival

• Bendamustine in combination with rituximab can be applied with comparable ORR

and OS rates as R-CHOP, but with lesser side effects

Reprinted from The Lancet, 381(9873), Rummel MJ, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent

and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial, 1203–10. Copyright 2013, with permission from Elsevier.


TREATMENT

MCL elderly survival rates (R-CHOP)

Remission duration Overall survival

• Rituximab as maintenance therapy every two months following R-CHOP chemotherapy

significantly improves PFS

From N Engl J Med, Kluin-Nelemans HC, et al. Treatment of Older Patients with Mantle-Cell Lymphoma, 367:520–31. Copyright © 2012 Massachusetts Medical


BORTEZOMIB IN MCL

VR-CAP vs. R-CHOP

No maintenance Therapy after induction!

59% improvement with VR-CAP vs. R-CHOP (hypothesised: 40% improvement)

Median PFS by investigator was 16.1 vs. 30.7 months with R-CHOP vs. VR-CAP

From N Engl J Med, Robak T, et al. Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma, 372:944–53. Copyright © 2015 Massachusetts Medical


FIRST LINE ELDERLY PATIENTS

Conclusion

In elderly patients with compromised organ function and performance score, conventional

immuno-chemotherapy is the first choice with ORR of ~90%

Fludarabin-containing regimens are inferior to R-CHOP in terms of OS

Rituximab as maintenance therapy every two months following R-CHOP chemotherapy

significantly improves PFS

Bendamustin in combination with Rituximab can be applied with comparable ORR and OS rates

as R-CHOP, but with lesser side effects

Bortezomib in combination with R-CAP (VR-CAP) shows better PFS compared to R-CHOP with

more (haemoto-) toxicity and may be a good option for aggressive (e.g. blastoid) MCL in elderly

patients not eligible for ASCT

In very frail patients Rituximab mono or Rituximab and oral Chlorambucil is an effective and well

tolerated regime, especially in low risk or rather indolent cases


TREATMENT

First Relapse / Refractory Disease

Immunochemotherapy

e.g. B-R

R-BAC

Targeted Approaches

Repeat First Line?

Consider: Allogeneic SCT

Immunochemotherapy

e.g. B-R, R-CHOP, R-BAC

Targeted Approaches

Repeat First Line?

Consider: R- Maintenance

Radioimmunotherapy

Immunochemotherapy

e.g. B-R (dose reduced)

Targeted Approaches Best

Supportive Care?

Higher Relapse

Targeted Approaches: Ibrutinib, Lenalidomide,

Temsirolimus, Bortezomib (preferable in combination with chemotherapy)

Alternatively: repeat previous therapy (long remissions)


Comorbidity

Performance Status


Comorbidity

Performance Status


Comorbidity

Performance Status

R, Rituximab, B-R, Bendamustine-Rituximab, R-CHOP, Rituximab/ Cyclophosphamide/ Doxorubicin/ Vincristine/Prednisone,

VR-CAP, Bortezomib/Rituximab/Cyclophosphamide/Doxorubicin/Prednisone

R-DHAP, Dexamethason/high-dose Cytarabine/Cisplatin, R-CVP- Rituximab/Cyclophosphamide/Prednison

R-BAC, Rituximab/Bendamustine/Cytarabine, SCT- Stem-Cell Transplantation

TARGETED SUBSTANCES

AT RELAPSE

Temsirolimus is registered in EU and has shown superiority over other agents in

heavily pre-treated patients with ORR of 23%, and PFS of 4.8 months

Hess G, et al. J Clin Oncol 27(23), 2009:3822–9. Reprinted with permission. © 2009 American Society of Clinical Oncology. All rights reserved.

TARGETED SUBSTANCES

AT RELAPSE

Lenalidomide

Lenalidomide

(n = 170)

IC

(n = 84)

Median PFS, mo (95% CI) 8.7 (5.5-12.1) 5.2 (3.6-6.9)

HR (95% CI) 0.61 (0.44-0.84); P = 0.004

Number of patients at riskLenalidomide

IC

170

84

86

31

63

15

36

7

27

5

20

4

16

4

12

2

7

0

1 1 0

1.0

0.8

0.6

0.4

0.2

0.0

Sur

viva

l pro

babi

lity

Progression-free survival, months

0.1

0.3

0.5

0.7

0.9

0 5 10 15 20 25 30 35 40 45 50 55

LenalidomideIC

Lenalidomide

8.7 mo

Control

5.2 mo

Patients with relapsed or refractory mantle cell lymphoma ineligible for intensive chemotherapy or stem-cell

transplantation have longer progression-free survival with lenalidomide compared to investigator's choice of monotherapy

Reprinted from The Lancet Oncol, 17(3), Trněný M, et al. Lenalidomide versus investigator's choice in relapsed or refractory mantle cell lymphoma (MCL-002;

SPRINT): a phase 2, randomised, multicentre trial, 319–31, Copyright 2016, with permission from Elsevier.

TARGETED SUBSTANCES

AT RELAPSE

Ibrutinib

TARGETED SUBSTANCES

AT RELAPSE

At a 2-year landmark, the PFS rate was 41% for ibrutinib versus 7% for temsirolimus

Investigator-assessed HR for ibrutinib versus temsirolimus was 0.43 (95% CI, 0.32-0.58)

ITT population

Median follow-up: 20 months

Ibrutinib Temsirolimus

Median PFS (months) 14.6 6.2

Hazard ratio (HR) 0.43

95% confidence interval (CI) 0.32-0.58

Log-rank p value < 0.0001

0 3 6 129 15

Months

18 21 24 27 30

0

30

10

20

40

50

60

70

80

90

100

% a

live

with

out p

rogr

essi

on

Temsirolimus

Ibrutinib

Reprinted from The Lancet, 387(10020), Dreyling M, et al. Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an

international, randomised, open-label, phase 3 study, 770–8, Copyright 2015, with permission from Elsevier.

Patients at riskIbrutinib 139 114 101 83 77 45 34 8 5 0 0Temsirolimus 141 93 69 45 33 19 11 3 1 0 0

TARGETED SUBSTANCES

AT RELAPSE

Adverse events ibrutinib

*AEs were updated with an estimated median follow-up of 26.7 months

Republished with permission of American Society of Hematology, from Blood, Wang ML, et al. 126(6), 2015, permission conveyed through Copyright Clearance Center, Inc.

OUTLOOK: TAILORED MEDICINE

First line MCL suggested therapeutic algorithm

High Highintermediate

Lowintermediate

Low

Mutational screening

MIPI-c risk

ASCTPost-treatment risk

evaluation: MRD

TP53,NOTCH1,

other

SOX11 negativewithout adverse

mutations

HD AraC +anthracyclin

+ biological agent

HD AraC +biological agent

HD AraC

MRD+ MRD-

Conventional treatment(low tumour load:watch and wait)

MRD+ MRD-Consolidation/maintenance

Observation

Dreyling M, et al. Haematologica 2016;101(2):104–14. Obtained from the Haematologica Journal website http://www.haematologica.org

THERAPY AT RELAPSE

Conclusion I

Immuno-chemotherapy is standard of care at relapse and is chosen depending on

patient fitness and age, comorbidities, earlier therapy and duration of response

The mTOR-inhibitor temsirolimus can achieve better ORR, PFS and OS compared to

mono-chemotherapy at relapsed or refractory disease

In relapsed or refractory disease ibrutinib increases ORR from 40% to 72% and PFS

(hazard ratio 0,43; median 8,4 months) compared to temsirolimus. OS is not affected

by ibrutinib (due to crossover)

Lenalidomide also increases ORR and PFS compared to physicians choice in relapsed

and refractory disease

THERAPY AT RELAPSE

Conclusion II

Bortezomib also shows promising activity in MCL as monotherapy or in combination,

yet no Phase III data is available in refractory or relapsed disease, e.g. a combination

of bortezomib and bendamustin + rituximab (BERT) shows high activity in a

Phase II study

Rituximab maintenance therapy after salvage immunochemotherapy leads to improved

PFS and can be discussed

If HD-Ctx and ASCT has not been performed as first line therapy, eligible patients

should be offered a HD-Ctx and ASCT after lymphoma remission in relapse

Young fit patients relapsing after HD-Ctx and ASCT should be offered an allogenic

transplantation if a donor is available

OUTLOOK: BCL-2 INHIBITION

Venetoclax

75%

(21%)

OR 38%

(CR 11%)

18%

(12%)

Davids MS, et al. J Clin Oncol, 35(8), 2017:826–33. Reprinted with permission. © 2017 American Society of Clinical Oncology. All rights reserved.

OUTLOOK: CHEMOTHERAPY

FREE COMBINATIONS?

First line: Rituximab-lenalidomide

From N Engl J Med, Ruan J, et al. Lenalidomide plus Rituximab as Initial Treatment for Mantle-Cell Lymphoma, 373:1835–44. Copyright © 2015 Massachusetts

Medical Society. Reprinted with permission from Massachusetts Medical Society.

Progression-free survival

OUTLOOK:

COMBINATION THERAPY

European MCL Network Study generation 2017

< 65 years > 60 years

R-HAD +/- Bortezomib

1. Relapse

2. Relapse (or not qualifying for R-HAD)

BeRT

BR-temsirolimusIbrutinib vs. temsirolimus

MCL elderly R2:

R-CHOP vs. R-CHOP/Ara-C

=> Rituximab M

+/-Lenalidomide

MCL younger:

R-CHOP/DHAP =>ASCT

R-CHOP/DHAP+I =>ASCT => I

R-CHOP/DHAP + I => I

MCL elderly I:

BR +/- Ibrutinib

=> Rituximab M

+/- Ibrutinib

> 65 years

THANK YOU!

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Mantle Cell Lymphoma - European Society for Medical Oncology